Up to 20% of idiopathic pulmonary fibrosis cases (IPF) are familial, comprising a syndrome known as Familial Interstitial Pneumonia (FIP). Short peripheral blood telomere length has been associated with sporadic IPF and FIP, and rare loss of function mutations in telomerase complex genes have been found in 15-20% of FIP families, however, investigations to date regarding the mechanisms linking telomerase dysfunction and telomere shortening with lung fibrosis have been largely unrevealing. Using whole-exome sequencing, we have recently identified loss-of-function mutations in regulator of telomere elongation helicase (RTEL1) that segregated with disease in 15 FIP families, and our preliminary data suggest impaired RTEL1 function leads to inefficient repair of DNA-damage in alveolar epithelial cells (AECs), leading to activation of p53 mediated cell- cycle arrest signalin programs that may contribute to AEC dysfunction in the context of pulmonary fibrosis. Using bioinformatics approaches, we identified a large group of FIP families (>50%) that carry rare variants in other genes related to cell cycle, DNA damage-repair, and p53 signaling, suggesting that abnormalities in these interrelated pathways may underlie genetic risk for a large subset of FIP families. In this proposal, we hypothesize that loss-of-function genetic variants in FIP-associated genes (including RTEL1) predispose to pulmonary fibrosis by altering DNA-damage repair and activating p53-mediated cell-cycle checkpoint arrest signaling in alveolar epithelial cells, resulting in impaired re-epithelialization following injury and progressive fibrotic remodeling. Our specific aims are: (1) To determine the role of Rtel in experimental lung fibrosis. (2) To determine the mechanisms through which RTEL1 regulates DNA damage-repair and cell survival/proliferation in response to injury, and (3) To determine whether DNA damage-repair capacity is altered in a large subset of FIP families and patients with sporadic IPF. To accomplish these aims, we will utilize Rtel deficient mouse models, RTEL1 deficient cell lines, primary cells from Rtel deficient mice, and primary cells from FIP and IPF patients. Together, these studies hold the promise of elucidating the role of DNA-damage repair and signaling in the development of pulmonary fibrosis, thus adding important new insights into disease pathogenesis.